Pulmonary Arterial Hypertension (PAH) is a chronic progressive disorder that leads to remodeling of blood vessels in the lung, low oxygen in the blood, right-sided heart failure and death. The poor prognosis and lack of effective PAH disease-modifying agents underscore the need for a better understanding of disease pathogenesis in order to identify new therapeutic approaches. This proposal addresses the molecular mechanisms involved in the development and progression of PAH. Specifically, we will examine - at both the physiological and the cellular level - the effects of a previously unrecognized, clinically relevant interaction between a proinflammatory cytokine [Macrophage Migration Inhibitory Factor (MIF)] and a thyroid hormone [Thyroxine (T4)] in PAH. We have identified MIF as a critical mediator in the development and progression of PAH and further, we have made the surprising discovery that T4 is a natural ligand for and inhibitor of MIF's inflammatory activity. We hypothesize that the dramatic increase in circulating MIF observed during the development of PAH alters the normal plasma MIF-free T4 ratio and underlies the high prevalence of hypothyroidism that has been reported in patients with pulmonary hypertension. The modified status of MIF and T4 in the plasma profoundly changes the interactions of these molecules with their respective cellular receptors leading to altered intracellular signaling and vascular cell proliferation. We outline a multi-faceted approach involving clinical studies, animal models and in vitro assessments. We will examine the MIF-T4 relationship in patients with PAH, both during disease progression and before/after a standardized exercise challenge. We will further examine the interrelationship between these molecules in both animal models of pulmonary vascular remodeling and at a cellular level to understand better the consequence of the interaction on intracellular signaling and cell replication. The long term goal of the project is to exploit the relationship between these molecules to develop new and more effective therapeutic approaches for the treatment this devastating disease. While this proposal focuses on the interactions of MIF and T4 in the pathogenesis of PAH, data achieved in the study will be directly relevant to other cardiopulmonary disease states in which MIF is increased including stroke, cardiovascular disease, myocardial infarction, pulmonary fibrosis and obstructive sleep apnea.